The exposure of animals to stressful stimuli activates endogenous mechanisms that result in analgesic responses, some of which are mediated by the central nervous system (CNS). Depending on the nature of the stimulus and the parameters of exposure, two types of stres-induced analgesic responses can be elicited by the CNS: opiate and non-opiate. In contrast to opiate-mediated responses, non-opiate responses are not blocked by opiate antagonists, do not develop tolerance to repeated exposures of the stressor, and do not exhibit cross-tolerance with morphine analgesia. Thus far, the mediators of non-opiate analgesia have not been identified. Drugs that interfere with the synthesis of brain histamine (HA) and drugs that block brain HA H2-receptors inhibit this response, whereas drugs that stimulate H2-receptors cause analgesia when injected directly into brain. Because HA has been recently identified within CNS neurons and is believed to function as a transmitter, these finding suggest that brain HA is a mediator of non-opiate analgesic mechanisms. The long-term goals of this project are to identify the HA-containing cells mediating non-opiate stress-induced analgesia, to map the pathways mediating these analgesic responses, to characterize these mechanisms neurochemically and pharmacologically, and to develop novel analgesic agents that act through histaminergic mechanism. Presently, the effects of several classes of drugs related to HA metabolism and HA receptors will be studied on opiate- and non-opiate footshock-induced analgesia (FSIA) to characterize further the role of HA in FSIA. Several experiments will identify the anatomical site where HA release comprises part of the non-opiate analgesic pathway: a) the levels of the H2-antagonist cimetidine will be measured in discrete regions of the CNS after various doses of peripherally-administered drug, b) the effects of hypophysectomy, adrenalectomy, spinalectomy and mid-collicular decerebration will be determined on the HA-mediated FSIA, and c) the effects of intraventricular, intrathecal, and intracerebral injections of cimetidine will be determined on the non-opiate FSIA. To explore the relationship between FSIA and neurochemical indices of brain HA, the effects of various regimens of footshock will be determined on the levels of HA and its metabolite, and on HA turnover rates in discrete regions of brain and spinal cord. These studies are necessary to characterize HA as a mediator of non-opiate analgesia, and may lead to the development of centrally-acting non-opiate analgesic agents.